Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a medical oncologist focusing on prostate cancer, and on this UroToday video today, we have the honor and pleasure of having Doctor and Professor Karim Fizazi here to talk to us about the data from the phase three PSMAfore trial with the Lutetium-177 PSMA-617 or PLUVICTO®, which got approved in the US for use prior to docetaxel chemotherapy in the metastatic castration-resistant prostate cancer.

Karim, welcome and thank you for joining us today.

Karim Fizazi: Thank you very much, Neeraj. So PSMAfore was a phase three trial for patients with metastatic castration-resistant disease who had already exhausted one second-generation androgen receptor pathway inhibitor, typically abiraterone or enzalutamide at this time. They had not received a taxane for castration-resistant disease, and they had PSMA-positive disease based on PSMA-PET evidence for that, at least one lesion had to be positive by PSMA-PET. And these patients were actually not immediate candidates to go for docetaxel chemotherapy for their progressing therapy because they had mostly in the lung disease. And this is actually reflected by patients' characteristics with very low proportion of those men having, for example, liver metastases.

So, these patients were randomized to receive either a second-generation receptor pathway inhibitor, abiraterone or enzalutamide, depending on what they had received first, or all Lutetium-PSMA for up to six cycles. One cycle being given once every six weeks. The radiographic progression-free survival was the primary endpoint.

And actually and very importantly, in this trial, a crossover was allowed and aggressively proposed, should I say, to patients and actually patients really willing to receive a crossover. The degree of crossover was very high. The trial is clearly positive by its primary endpoint, confirming the first phase three trial, called VISION in more advanced disease. And actually, patients in the Lutetium-PSMA arm could enjoy approximately a 60% reduction in the risk of progression or death as compared to those from the control arm.

For those of you who like to see medians, actually they were approximately doubled, six months or even less in the control arm with the second AR pathway inhibitor and more than 12 months in the Lutetium-PSMA arm. So, the trial is positive but also and important, we clearly gave Lutetium-PSMA as a salvage treatment, as I said, to patients in the control arm who actually developed progression on their second AR pathway inhibitor.

Neeraj Agarwal: Thank you, Karim, for showing the design and the primary endpoint of the trial, which was clearly met with doubling of progression-free survival from less than six months to 12 months when Lutetium therapy was given to these patients. You mentioned a significant crossover of patients from the control ARPI arm to the Lutetium arm. Can you please tell us more about the control and what effect it had on the overall survival?

Karim Fizazi: This is a key question because, and I'm glad you are asking that Neeraj, overall survival was not significantly improved in PSMAfore, but truly this was almost expected because at the end of the day, what we did in this trial was randomizing men who agreed to either receive Lutetium-PSMA immediately if they were in this experimental arm versus Lutetium-PSMA in say six months' time because this is present minus the time it took for their cancer to progress.

And most patients who developed a progression event in the control arm actually decided to receive crossover Lutetium-PSMA rather than going for something else, which, of course, is totally understandable and given the relatively safe profile of a treatment and its known efficacy in later stages. So, in a trial where you are really comparing active drug today versus active drug in six months' time, no wonder that we don't really see overall survival improved.

So, again, I was really not surprised. Having said that, this placed the trial and the treatment in a difficult setting regarding the agencies, regulators, but also payers because they like to see overall survival. But to be honest, at this time, because this was based on intense discussion amongst us, I think this was a fair decision towards patients because we already knew that this treatment was active and patients also knew that. So, I think it was a fair deal to patients who agreed on to be enrolled in the trial to propose them this crossover.

Neeraj Agarwal: So, that brings the next question then, how do we estimate or assess benefit of a treatment which is associated with radiographic progression free survival benefit? It's a huge benefit, a hazard ratio of less than 0.5, 0.43, 6-month absolute benefit in RPFS and overall survival is not there because of the significant crossover. So, how else we can assess benefit?

Karim Fizazi: Thank you, Neeraj. Because overall survival is a key question, and here I'm glad that in this trial, similar to many recent other trials, we looked at clinical benefit as directly measured from a patient perspective. And this is why PROs are so important. For example, we looked at quality of life or time to degradation of quality of life in the trial using the FACT-P questionnaire, but also others. And we saw a clear benefit favoring the immediate radiation PSMA arm with approximately 50% reduction in the risk of deterioration in quality of life as compared to the second-generation receptor pathway inhibitor.

Also, I told you that we mostly randomize and include patients who had indolent disease at baseline, but with time, of course, some of them will develop pain mostly from the bone because prostate cancer at the end of the day is a bone disease when it's metastatic.

And I'm happy to say that the time to pain degradation was also significantly improved. Favoring again, Lutetium-PSMA, as was time to symptom-related events with approximately a 60% reduction in the risk. And here we're truly measuring bone morbidity, aggressive disease, direct consequences to the patients, and by the way, direct consequences to the society because SRE means hospitalizations for spinal cord compression or for major pain, radiation therapy being needed, et cetera, et cetera. So, it means bad thing to the patient, but also money to be used from either patient, his insurance, or the social security system depending on where you live. So, I think all those are very important to measure direct benefit that we're providing to patients in situations where, basically, overall survival is not really helpful, again, because we used this aggressive crossover.

Neeraj Agarwal: Thank you, Karim, for summarizing the results of the phase three PSMAfore trial, which assessed the efficacy of Lutetium-PSMA therapy in patients with metastatic CRPC who had prior disease progression on an ARPI. And you showed through the PSMAfore trial, doubling of radiographic progression-free survival and a significant improvement in the quality of life and delay of cancer-related pain.
Overall survival was not positive, likely because a significant number of patients who had disease progression on the ARPI control arm were allowed to cross over to the Lutetium therapy arm. Any new safety signal, Karim, before we conclude this discussion?

Karim Fizazi: Generally speaking, Lutetium-PSMA is well tolerated. I think it's fair to say that. Having said that, some patients, actually, approximately 40% of them will develop some dry mouth. In most patients it's not a big issue. I was a bit anxious when I first started this treatment more than five years ago, having in mind patients with head and neck cancer who receive external beam radiation for example, but it's clearly different. That's reassuring to me.

Having said that, a few patients will develop more aggressive dry mouth. So, you need to pay attention, you need to tell them, of course, but also pay attention to it when it happens. And if it happens to be longer than usual, let's say, then probably we should stop. That's one thing.

Also, the hematological toxicity is something we should pay attention to, probably even more in the VISION indication when patients have widespread dissemination in their bone and bone marrow. So, you are really radiating the entire skeleton in some of these men. Probably less true in the PSMAfore indication, and probably this is a good reason for me to actually use Lutetium-PSMA not too late in the course of a disease.

So, those are things we should mostly pay attention to in terms of side effect. And, of course, some other trials in earlier stages will tell you whether eventually we see or we don't see an excess in myelodysplasia or leukemia, for example, which theoretically happen when you're using whole body radiation.

Neeraj Agarwal: Well, thank you very much. That's a very nice summary of the side effects of Lutetium and how to manage them. So, I would like to thank you again for joining us and walking us through the results of the phase three PSMAfore trial, which led to FDA approval of Lutetium-PSMA therapy or PLUVICTO® for our patients with metastatic CRPC prior to receiving docetaxel chemotherapy in this setting. Thank you.

Karim Fizazi: Thank you very much, Neeraj.